EP0937043A1

EP0937043A1 - Novel substituted tetrahydropyridin derivatives, method of preparation and pharmaceutical compositions containing them

Info

Publication number: EP0937043A1
Application number: EP97948974A
Authority: EP
Inventors: Christian Marazano; Delphine Compere; C. Bhupesh Das; Jean Lepagnol
Original assignee: ADIR SARL
Current assignee: Laboratoires Servier SAS
Priority date: 1996-12-05
Filing date: 1997-12-02
Publication date: 1999-08-25
Anticipated expiration: 2017-12-02
Also published as: NO992731L; EP0937043B1; CA2274133C; CN1126739C; AU719208B2; ATE214051T1; HUP0001773A2; US6232319B1; HK1023346A1; NO313589B1; NO992731D0; WO1998024765A1; FR2756826B1; ES2172023T3; HUP0001773A3; PL189372B1; NZ336111A; JP2001505214A; FR2756826A1; DE69710909D1

Abstract

The invention concerns compounds of general formula (I): in which R, R1, R2, X and Y are as defined in the description, their geometrical and/or optical isomers, and their additive salts to a pharmaceutically acceptable acid or base. Drugs.

Description

NEW SUBSTITUTED TETRAHYDROPYRIDINIC DERIVATIVES,

THEIR PREPARATION PROCESS

AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

The present invention relates to new substituted tetrahydropyridine derivatives, their preparation process and the pharmaceutical compositions containing them.

Many studies in the literature describe the synthesis of compounds derived from lobelin as alkaloids capable of interacting with nicotinic receptors. Mention may in particular be made of Hootelé for the synthesis of sedinone and sedacrine (Hootelé C,

Driessens F., Can. J. Chem., 1991, 69 (2), pp. 211-17) and Natsume for the synthesis of sedinin (Natsume M., Ogawa M., Hétérocycles, 1985, 23 (4), pp. 831-4).

The compounds of the present invention are new and particularly advantageous from a pharmacological point of view for their specific interaction with nicotinic receptors, finding their application in the treatment of diseases associated with cerebral aging.

The aging of the population by increasing life expectancy has at the same time led to a large increase in the incidence of age-related neurodegenerative diseases, in particular Alzheimer's disease. The main clinical manifestations of cerebral aging and especially neurodegenerative diseases are deficits in memory and cognitive functions which can lead to dementia. It is widely demonstrated that among the various neurotransmitters, acetylcholine holds a preponderant place in memory functions and that the cholinergic neuronal pathways are dramatically destroyed during certain neurodegenerative diseases or in activation deficit during brain aging. This is why many therapeutic approaches have aimed at preventing the destruction of the neuromediator via acetylcholine-esterase or have sought to replace the deficient neuromediator. In the latter Ocas, the cholinergic agonists proposed were of the muscarinic type, specific for the postsynaptic M1 receptors. Recently, it has been shown that in fact the cholinergic attack linked to Alzheimer's disease affected more the neurons carrying the nicotinic receptors (N) than those carrying the muscaric receptors (Schroder et al., In "Alzheimer disease: therapeutic strategies ”, Birkhauser Boston ed., 1994, 181-185). In addition, many studies have shown that nicotine has memory-enhancing properties

(Warburton, Prog. Neuropsychopharmacol, 1992, 16, 181-191) and that these properties are exerted as much on memory functions (Levin and Torry, Psychopharmacol., 1996, 123, 88-97) as on faculties of attention and vigilance (Turchi et al., Psychopharmacol., 1995, H8, 195-205). In addition, nicotine exerts neuroprotective effects with regard to excitotoxic agents such as glutamate (Akaike et al., Brain

Res., 1994, 644. 181-187). All of these data are most likely to be linked to epidemiological studies which have shown a lower incidence of Alzheimer's or Parkinson's disease in smokers.

Although nicotinic receptors are not yet fully classified, it is well demonstrated today that these receptors can be of different natures and together can have very diverse electrophysiological properties (for review: Williams et al., Drug News Perspect., 1994, 7, 205-223). This is why nicotine has both beneficial promnesic properties demonstrated in the Alzheimer patient (Wilson et al., 1995, 5_1, 509-514) and deleterious addictive properties by activation of receptors with variable inactivation kinetics. .

Apart from nicotine itself, other nicotinic agonists have been described, including lobelin which has powerful promnesic properties (Decker et al., Pharmacol. Biochem. Behav., 45, 571-576) but unlike nicotine, which binds preferentially to certain subtypes of rapid desensitization receptors, named al (Marks et al., J. Pharmacol. Exp. Ther., 1986, 30, 427-436). This is why lobelin is potentially devoid of addictive potential.

The compounds of the present invention have therefore been synthesized as nicotinic ligands having promnesic properties for the treatment of memory deficits associated with cerebral aging and with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Pick's disease, Korsakoff's disease and frontal and subcortical dementias.

More specifically, the present invention relates to the compounds of formula (I):

in which :

- X represents a hydrogen atom,

Y represents a hydroxy group, or X and Y together form an oxo group,

- R represents a linear or branched (Cι-C ₆ ) alkyl group or a phenyl group optionally substituted by one or more halogen atoms or one or more linear or branched (Cι-C ₆ ) alkyl groups, alkoxy (Cι-C ₆ ), linear or branched polyhalo (-C ₆ ) alkyl, or hydroxy,

- R ¹ represents a hydrogen atom or a group of formula (II):

" ^CH 2 -J - ^R3 (H)

X 'Y' in which:

X 'represents a hydrogen atom,

Y 'represents a hydroxy group, or X' and Y 'simultaneously represent a linear or branched alkoxy group (Cι-C ₆ ), or X' and Y 'together form an oxo group or a linear alkylene dioxy group (Cι-C) or branched,

R ³ represents a linear or branched (Cι-C ₆ ) alkoxy group, or a phenyl group optionally substituted by one or more halogen atoms, or one or more linear or branched (Cι-C ₆ ) alkyl groups, alkoxy (Cι -C ₆ ), linear or branched polyhaloalkyl (C _\ - Cβ) or hydroxy, - R ² represents a hydrogen atom, a linear or branched alkyl group (Cι-C ₆ ), optionally substituted by one or more groups, identical or different, optionally substituted aryl, alkoxy (Cι-C ₆ ) linear or branched, or hydroxy, 9 being understood that when R and R simultaneously represent a methyl group, X represents a hydrogen atom, Y represents a hydroxy group and R ¹ represents a group of formula (II) where X 'represents a hydrogen atom and Y' a hydroxy group, then R ^′ cannot represent a phenyl group,

their isomers and their addition salts with a pharmaceutically acceptable acid or base.

Optionally substituted by aryl, is meant phenyl or naphthyl, each of those groups being optionally substituted by one or more halogen atoms or one or more alkyl _(Cι-C6) straight or branched alkoxy _(Cι-C6), polyhalogeno alkyl (Cι-C ₆ ) linear or branched, or hydroxy.

Among the pharmaceutically acceptable acids, non-limiting mention may be made of hydrochloric, hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methane acids. sulfonic, camphoric, etc.

Among the pharmaceutically acceptable bases, non-limiting mention may be made of sodium hydroxide, potassium hydroxide, triethylamine, tertbutylamine, etc.

The present invention preferably relates to the compounds of formula (I) for which X represents a hydrogen atom and Y a hydroxy group, and more particularly the compounds of formula (I) for which X represents a hydrogen atom, Y a group hydroxy and R ¹ represents a hydrogen atom, or a group of formula (II):

- CH, - C - R ³ (π)

² / \ X 'Y' where X ', Y' and R ³ are as defined above.

The invention also extends to the process for preparing the compounds of formula (I) characterized in that a compound of formula (III) is used as starting material: in which R represents a linear or branched alkyl (Cι-C ₆ ) or optionally substituted aryl group, which is reacted with sodium borohydride in the presence of sodium hydroxide to obtain the compound of formula (IV):

in which R is as defined above, which, subjected to the Reformatsky BrZnCH ₂ COOEt reagent, leads to the compound of formula

(V):

in which R ⁴ has the same definition as before,

which is successively subjected to the action of dimethylthexylchlorosilane then to that of lithium aluminum hydride, to lead to the compound of formula (VI):

in which R ⁴ is as defined above, and Thex represents a group

(l, l, 2) -trimethyl-propyl, which is oxidized according to Swern, to yield the compound of formula (Vu): in which R and Thex are defined as above, which is subjected to the action of the magnesium RMgBr where R is as defined in formula (I), to lead to the compound of formula (VIII):

in which R, R and Thex are as defined above, which is optionally subjected to an oxidizing agent, to yield the compound of formula

(IX):

in which R, R ⁴ and Thex have the same definition as above, all of the compounds (VIII) and (IX) forming the compound of formula (X):

in which R, R, X, Y and Thex are as defined above, compound of formula (X) which is hydrolyzed in acid medium, to lead to the compound of formula (Va), special case of the compounds of formula (I):

in which R, X, Y and R are as defined above, which is: either treated, when X represents a hydrogen atom and Y a hydroxy group, with hydrogen in the presence of palladium on carbon, to obtain the compound of formula (I / b), special case of the compounds of formula (I) :

in which R is as defined above, is treated with a diphenylalkylsulfonium tetrafluoroborate of formula (XI)

in which R ⁵ represents a linear or branched alkyl group (Cι-C ₆ ), to result in the compound of formula (XII):

in which R, R, R, X and Y are as defined above, compound of formula (XII) which is subjected to the action of potassium tertbutanolate in tertbutanol, to lead to the compound of formula (I c), case particular of the compounds of formula (I):

in which R, X, Y and R ^' are as defined above, which is, in the case where X represents a hydrogen atom and Y a hydroxy group treated with metachloroperbenzoic acid, to obtain the compound of formula (XIII ):

in which R and R ⁵ have the same definition as before, which is subjected to the action of trifluoroacetic anhydride, to lead to the compound of formula (XIV):

in which R and R ^' are as defined above, which are treated with the Reformatsky reagent BrZnCH ₂ COOR ⁶ where R ⁶ represents a linear or branched (C] -C ₆ ) alkyl group, to obtain the compound of formula (I / d), special case of the compounds of formula (I):

in which R, R ^" and R have the same definition as before, which is successively subjected to the Weinreb reagent. N - Al ^ TP ^{U1S has} 1 action

Me- ~ Me

of a lithian R ⁷ -Li where R ⁷ represents a phenyl group optionally substituted by one or more halogen atoms or one or more alkyl groups (Cι-C ₆ ) linear or branched, alkoxy (Cι-C ₆ ), polyhaloalkyl (C] -C ₆ ) linear or branched, hydroxy, to yield the compound of formula (I / e), special case of the compounds of formula (I):

in which R, R ^" and R are as defined above, which is: either subjected to an oxidizing agent, to yield the compound of formula (I / f), special case of the compounds of formula (I):

in which R, R ⁵ and R ⁷ have the same definition as above, either subjected to a reducing agent, to lead to the compound of formula (I / g), special case of the compounds of formula (I):

in which R, R ^" and R are as defined above, is protected in the form of acetal by the action of an alcohol in an acid medium, to obtain the compound of formula (I / h), special case of the compounds of formula (I):

in which R, R ⁵ and R ⁷ are as defined above, and X "and Y" simultaneously represent a linear or branched alkoxy group (Cι-C ₆ ) or together form a linear or branched alkylenedioxy group (Cj-C ₄ ) ,

the compounds (I / a) to (I / h) forming all of the compounds of the invention which are purified, if necessary, according to a conventional purification technique, which can, if desired, be separated in their various optical isomers or salified with a pharmaceutically acceptable acid or base.

The present invention also relates to the synthesis intermediates of formula (V),

(XII) and (XIII) described in the process explained above.

The starting pyridinium salts used in the process described above are accessible to those skilled in the art according to processes well known in the literature, for example that described by: Y. Génisson, C. Marazano, M. Mehmandoust, D. Gnecco & BC Das, Synlett, 1992, p. 431.

The compounds of formula (I) have interesting pharmacological properties.

By their memory-promoting properties and by their preferential affinity for the nicotinic al receptors, the compounds of the present invention are therefore useful for the treatment of memory deficits linked to cerebral aging and to neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Pick's disease, Korsakoff's disease and frontal and subcortical dementias.

The present invention also relates to pharmaceutical compositions containing the products of formula (I), their optical isomers or one of their addition salts with a pharmaceutically acceptable base or acid, alone or in combination with one or more excipients or vehicles inert, non-toxic.

Among the pharmaceutical compositions according to the invention, particular mention will be made of those which are suitable for oral, parenteral, nasal, rectal, perlingual, ocular or respiratory administration, and in particular simple or coated tablets, sublingual tablets, sachets, packages, capsules, glossettes, tablets, suppositories, creams, ointments, dermal gels, injectable or drinkable preparations, aerosols, eye or nasal drops.

The useful dosage varies according to the age and weight of the patient, the route of administration, the nature of the therapeutic indication and any associated treatments and ranges between

1 and 500 mg per day in one or more administrations.

The following examples illustrate the invention but do not limit it in any way.

EXAMPLE 1: (lS, l'S, 2 "S) -2- [l- (2-Hydroxy-1-phenyl-ethyl) -l, 2,3,6-tetrahydro-pyridin-2-yI] -l-phenyl -ethanol

Stage_A: (3S, 8aS) -3-Phenyl-2,3,8,8a-tetrahydro- [5H] -oxazolo [3,2-a] pyridine

42.5 mmol of (l'S) -l- (2-hydroxy-1-phenyl-ethyl) -pyridinium chloride dissolved in water are added slowly to 132 mmol of sodium borohydride in solution in a two-phase 5N soda system (100 ml) and ether (400 ml) at room temperature. After one hour of vigorous magnetic stirring, the organic phase is decanted and quickly filtered through a short column of alumina (60 g). After evaporation of the solvent under reduced pressure, the oxazolidine is obtained. Orange-red oil

Stage B: (L'S, 2 "S) - [1- (2-Hydroxy-1-phenyl-ethyl) -2- (ethoxycarbonyI-methyl)] -

1,2,3,6-tetrahydropyridine

118.61 mmol of (3S, 8aS) -3-phenyl-2,3,8,8a-tetrahydro- [5H] -oxazolo [3,2-a] pyridine dissolved in anhydrous ether (180 ml) are added dropwise to the Reformatsky BrZnCH2COOEt reagent (474 ml, 474 mmol) placed at 0 ° C under an argon atmosphere and magnetic stirring. When the addition is complete, the temperature is allowed to rise to 25 ° C. and then stirring is maintained at this temperature overnight. The reaction mixture is poured onto a saturated solution of ammonium chloride at 0 ° C. then filtered through a bϋchner filter in order to remove the insoluble precipitates. The organic phase is extracted with ether then with ethyl acetate and finally dried over magnesium sulfate. After evaporation of the solvent under reduced pressure, the mixture of tetrahydropyridines is obtained in the proportions 60/40 respectively (determined by gas chromatography after acetylation of the reaction crude). The two diastereoisomers are separated by chromatography on silica gel eluted with a gradient of 400 ml of ethyl acetate / heptane (0/100 to 50/50 of 5% to 5%). Orange yellow oil

HR (IC) (Methane): Cι ₇ H ₂₄ N0 ₃ Calculated: 290.1765 Found: 290.1769

SiadeÇ: (l'S, 2 ^M S) - (l- {2- [Dimethyl- (1,1,2,2-trimethylpropyl) -silanyloxy] -l-phenyl-ethyl} -2- {ethoxycarbonyl-methyl}) - l, 2,3,6-tetrahydropyridine

30.65 mmol of (S, 2 "S) - [1- (2-hydroxy-1-phenyl-ethyl) -2- (ethoxycarbonyl-methyl)] - 1,2,3,6-tetrahydropyridine are diluted in anhydrous dichloromethane (70 ml) then placed at 0 ° C. under an argon atmosphere. Dimethylthexylchlorosilane (1.5 eq, 9.0 ml, 45.98 mmol) is added and then triethylamine (2.5 eq, 10.8). ml, 76.64 mmol) as well as a catalytic amount of dimethylaminopyridine. The temperature is allowed to rise to 25 ° C then stirring is maintained at this temperature overnight. The reaction mixture is poured onto a saturated solution of ammonium chloride at 0 ° C. The organic phase is extracted with dichloromethane and then dried over magnesium sulfate. After evaporation of the solvent under reduced pressure, the reaction crude is filtered through a short column of alumina (140 g) eluted with a gradient of ethyl acetate / heptane (0/100 to 30/70 from 10% to 10% ). The silylated mono-alkyl derivative is thus isolated. Yellow oil [a] _D : + 24 (c = 1.7, CHCl ₃ )

Stage D: (l ^, S, 2 "S) -2- (l- {2- [Dimethyl- (l, l, 2-trimethylpropyl) -silanyloxy] -l-phenyl-ethyl} -l, 2,3, 6-tetrahydropyridin-2-yl) ethanoI

27.45 mmol of (l'S, 2 "S) - (l- {2- [dimethyl- (1,1,2-trimethylpropyl) -silanyloxy] -l-phenylethyl} -2- {ethoxycarbonyl-methyl}) -1,2,3,6-tetrahydropyridine are diluted in anhydrous THF (90 ml) and placed at 0 ° C. with magnetic stirring. The lithium aluminum hydride is slowly added (1.5 eq, 2, 56 g, 41.17 mmol), the temperature is allowed to rise to 25 ° C. and stirring overnight. When the reaction is complete, ethyl acetate is added and then a few drops of water to destroy the hydride excess. The solution obtained is filtered through celite, rinsed with ethyl acetate then with methanol. The filtrate is dried over magnesium sulphate and evaporated under reduced pressure. The crude reaction product is then purified by filtration on a short alumina column (1 10 g) eluted with an ethyl acetate / heptane gradient (0/100 to 20/80 of 5% to 5%). The reduced silylated mono-alkyl is thus isolated. blade

HR (IC) (Methane): C ₂₃ H ₄ oN0 ₂ If Calculated: 390.2828 Found: 390.2803

[a] _D : - ll (c ≈ 0.65, CHCl ₃ )

Sjade E: (l'S, 2 ' ^, S) -2- (l- {2- [Dimethyl- (1,1,2-trimethylpropyl) -silanyloxy] -l-phenyl-ethyl} -l, 2,3,6 -tetrahydropyridin-2-yl) -ethanal Oxalyl chloride (4 eq, 8.40 ml, 97.56 mmol) dissolved in anhydrous dichloromethane (180 ml) is cooled to -78 ° C. Dimethyl sulfoxide (6 eq, 10.40 ml, 146.34 mmol) diluted with anhydrous dichloromethane (180 ml) is added, with stirring and under an argon atmosphere. After 10 minutes, 24.39 mmol of (L'S, 2 "S) -2- (1- (2-Dimethyl- (1, 1, 2-trimethylpropyl) -silanyloxy] - 1 -phenyl-ethyl) are added dropwise } - 1, 2,3, 6-tetrahydropyridin-2-yl) -ethanol dissolved in anhydrous dichlorometane (30 ml) The magnetic stirring is maintained at -78 ° C for 15 minutes. Then triethylamine (8 eq, 27.5 ml, 195.12 mmol) and the reaction mixture is allowed to return to ambient temperature, after addition of water, the organic phase is extracted with dichloromethane, dried over magnesium sulphate and evaporated under reduced pressure.

The aldehyde obtained is directly reacted, taking into account its instability.

Stage F: (L'S, 2 ^,, S) -2- (l- {2- [Dimethyl- (1,1,2-trimethylpropyl) -silanyloxy] -l-phenylethyl} -l, 2,3,6 -tetrahydropyridin-2-yl) -l-phenyl-ethanol

Phenylmagnesium bromide (1.5 eq, 61 ml, 36.59 mmol) is poured into a three-necked flask under an argon atmosphere and magnetic stirring at 0 ° C. The gross product of the Swern reaction

(9.44 g, 24.39 mmol) diluted in anhydrous ether (80 ml) is added dropwise via an ampoule of bromine. When the addition is complete, the temperature is allowed to rise to 25 ° C. and then stirring is maintained at this temperature overnight. The reaction mixture is then poured onto a saturated solution of ammonium chloride at 0 ° C. The organic phase is extracted with ether then with dichloromethane and finally dried over magnesium sulfate. After evaporation of the solvent under reduced pressure, the mixture of alcohols is obtained in the proportions 60/40 respectively (determined by integration of the protons in NMR). The two diastereoisomers are separated by chromatography on alumina (360 g) eluted with a gradient of 400 ml of ethyl acetate / heptane (0/100 to 5/95 of 1% in 1% then 5/95 to 20/80 from 5% to 5%). The majority diastereoisomer is isolated.

Brown paste

HR (IC) (Methane): C ₂₉ H ₄₄ N0 ₂ If Calculated: 466.3141 Found: 466.3152 [a] _D : - 18 (c = 0.22, CHCl ₃ ) Stage G: (lS, l ^, S, 2 "S) -2-ri- (2-Hvdroxv-l-phenvl-éthvl) -l, 2 _< 3,6-tetrahvdro-pvridin-2- y 1] - 1 -phenyl-ethanol

9.81 mmol of (L'S, 2 "S) -2- (l- {2- [Dimethyl- (1,1,2-trimethylpropyl) -silanyloxy] -l-phenyl-ethyl} - 1,2,3, 6-tetrahydropyridin-2-yl) -1-phenyl-ethanol are diluted in a mixture of hydrochloric acid / water / tetrahydrofuran in the proportions 3/1/1. The whole is left overnight under magnetic stirring at room temperature. The reaction medium is then extracted in the presence of potassium carbonate, with ether and then with dichloromethane. The organic phase is dried over magnesium sulphate and evaporated under reduced pressure. The crude reaction product is then filtered through a short column of alumina ( 95 g) eluted with a gradient of ethyl acetate / heptane (0/100 to 100/0 of 10% in 10%) then of methanol / dichloromethane (0/100 to 5/95 of 1% in 1%) The diol is thus isolated Yellow oil

HR (IC) (Methane): C _2] H ₂₆ N0 ₂ Calculated: 324.1964 Found: 324.1965

[a] _D : - 49 (c = l, l, CHCl ₃ )

EXAMPLE 2: (lR, l ^, S, 2 ^M S) -2- [l- (2-Hydroxy-l-phenyI-ethyl) -l, 2,3,6-tetrahydro-pyridin-2-yl] - 1 -phenyl-ethanol

The same method is used as for Example 1, choosing the minority diastereoisomer at stage F.

Yellow oil

HR (IC) (Methane): C ₂₁ H ₂₆ N0 ₂

Calculated: 324.1963

Found: 324.1941 [a] _D : + 52 (c = 2.4, CHCl ₃ )

Examples 3 to 6 are obtained using the same process as for Example 1, taking the appropriate magnesian in stage F. EXAMPLE 3: (lR, l ^, S, 2 "S) -l- [l- (2-Hydroxy-l-phenyl-ethyl) -l, 2,3,6-tetrahydro-pyridin-2-yl] -propanol -2

EXAMPLE 4: (1R, S, 2 "S) -l- [1- (2-Hydroxy-1-phenyl-ethyl) -l, 2,3,6-tetrahydro-pyridin-2-yl] -4-methyl -pentanol-2

EXAMPLE 5: (lS, l ^* S, 2 "S) -2- [l- (2-Hydroxy-l-phenyl-ethyl) -l, 2,3,6-tetrahydro-pyridin-2-yl] -l - (4-methyl-phenyl) -ethanol

EXAMPLE 6: (lS, l ^, S, 2 "S) -2- [l- (2-Hydroxy-l-phenyl-ethyl) -l, 2,3,6- tetrahydropyridin-2-yI] -l- ( 3-trifluoromethyl-phenyl) -ethanol

EXAMPLE 7: (lS, 2 "S) -2- (l-Methyl-1,2,3,6-tetrahydropyridin-2-yl) -1-phenylethanol

Sjade A: (lS, 2 ^M S) -2- [l-Methyl-l- (2-hydroxy-1-phenyl-ethyl) -l, 2,3,6-tetrahydro pyridinium-2-yl] -l- phenyl-ethanol-tetrafluoroborate

15.3 mmol of the compound of Example 1 are dissolved in distilled acetonitrile (160 ml). The diphenylmethyl sulfonium tetrafluoroborate (1.1 eq, 6.67 g, 21.09 mmol) is added with magnetic stirring and the whole is brought to reflux for 48 hours. After evaporation of the solvent under reduced pressure, the reaction crude is chromatographed on alumina (195 g) eluted with a gradient of 200 ml of ethyl acetate / heptane (0/100 to 50/50 from 10% to 10%) in order to to remove the diphenyl sulfide and the unreacted product, then with a gradient of 100 ml of methanol / dichloromethane (0/100 to 5/95 of 0.5% to 0.5% then of 5/95 to 50/50 from 5% to 5%). The methyl product is thus isolated.

Light beige foam

Stage B: (lS.2 "S) -2- (l-MethvI-l, 2,3,6-tetrahvdropyridin-2-vl) -l-phenvl-ethanol

3.56 mmol of the salt obtained in stage A are dissolved in distilled tert-butanol (40 ml). Add potassium tert-butanolate (1.5 eq, 600 mg, 5.34 mmol) previously sublimed (145 ° C, P = 0.6 mm Hg). The whole is brought to reflux for 2 hours. The cooled reaction mixture is poured onto a saturated chloride solution ammonium, extracted with dichloromethane and dried over magnesium sulfate. The manipulation is thus reproduced 3 times. After evaporation of the solvent under reduced pressure, the crude is chromatographed on alumina (70 g) eluted with a gradient of ethyl acetate / heptane (0/100 to 50/50 of 10% to 10%) then methanol / dichloromethane ( 0/100 to 6/94 from 0.5% to 0.5%).

Orange yellow oil HR (IE): C, ₄ H ₁₉ NO Calculated: 217.1467 Found: 217.1464

EXAMPLE 8 (1R, 2 "S) -2- (1-Methyl-1,2,3,6-tetrahydropyridin-2-yl) -1-phenylethanol

The procedure is as for Example 7 starting from the compound of Example 2. Orange-yellow oil HR (IE): C ₁₄ H, ₉ NO Calculated: 217.1467

Found: 217.1466

EXAMPLE 9 (2 "S) -2-Benzoylmethyl-1-methyl-1,2,3,6-tetrahydropyridine

The procedure is as in Stage E of Example 1 starting from the compound of Example 7 or 8.

EXAMPLE 10 (lR.2 "S) -l-ri-Methvl-1,2,3,6-tetrahvdropvridin-2-vI] -propanol-2

The procedure is as for Example 7 starting from the compound of Example 3.

EXAMPLE 11: (lS.2 "S) -2-ri-Methyl-1,2,3,6-tetrahvdropyridin-2-vll-l- (4-methvl-phenyl) -ethanol

The procedure is as for Example 7 starting from the compound of Example 5.

EXAMPLE 12: (2 "S) -2- (4-Methylbenzoylmethyl) -1-methyl-1,2,3,6-tetrahvdro pyridine The procedure is carried out as in stage E of Example 1 starting from the compound of Example 11.

EXAMPLE 13: (1S, 2 "S) -2- (1-Methyl-6-ethoxycarbonylmethyl-1,2,3,6-tetrahydropyridin-2-yl) -1-phenyl-ethanol

Stage A: (lS, 2 "S) -2- (l-Methyl-1,2,3,6-tetrahydro-pyridin-2-yl) -l-phenyl-ethanol, N-oxide

1 mmol of the compound of Example 7 is diluted in anhydrous dichloromethane (10 ml), and placed at 0 ° C with magnetic stirring. Meta-chloroperbenzoic acid (1.5 eq, 371 mg, 1.5 mmol) is added. After 15 minutes, the whole is rapidly filtered through a short column of alumina (60 times the theoretical weight) eluted with a methanol / dichloromethane gradient (0/100 to 5/95 from 1% to 1%). After evaporation of the solvent under reduced pressure, the N-oxide is isolated which is immediately reacted.

Stage B: (1S, 2 "S) -2- (1-methyl-2,3-dihydropyridinium-2-yl) -l- phenyl-ethane trifluoroacetate

1 mmol of the N-oxide obtained in stage A is taken up in anhydrous dichloromethane (10 ml) and the medium is placed at 0 ° C. Trifluoroacetic anhydride is added slowly

(2.5 eq, 0.35 ml, 2.5 mmol). The reaction is left for 20 to 30 minutes at 0 ° C. The solvent and excess reagent are evaporated under reduced pressure to provide the dihydropyridinium salt. In view of its instability, the compound is directly alkylated.

Stage C: (IS, 2 "S) -2- (1-Methyl-6-ethoxycarbonylmethyl-1,2,3,6-tetrahydropyridin-2-yl) -1-phenyl-ethanoI

The dihydropyridinium salt obtained in stage B is diluted with anhydrous dichloromethane (10 ml) and added dropwise to a 1 molar solution of Reformatsky reagent (5 eq, 5 ml, 5 mmol) placed at 0 ° C. under an atmosphere of argon and magnetic stirring. When the addition is complete, the temperature is allowed to rise to 25 ° C. and then stirring is maintained at this temperature overnight. The reaction mixture is poured onto a saturated solution of ammonium chloride at 0 ° C. The organic phase is extracted with dichloromethane and then dried over magnesium sulfate. After evaporation of the solvent under reduced pressure, the crude reaction product is filtered through a very short column of alumina eluted with a mixture of ethyl acetate / heptane (50/50). An inseparable mixture of diastereoisomers (182 mg, 0.60 mmol) is then obtained in the proportions 60/40 (determined by integration of the protons in NMR). Yellow oil SM (IC) (isobutane): m / z

360 ([M + 57] ⁺ , 7), 304 ([M + H] ⁺ , 100), 216 (fM-CH ₂ COOCH ₂ CH ₃ ] ⁺ , 8)

EXAMPLE 14: (1R, 2 "S) -1- (1-Methyl-6-ethoxycarbonylmethyl-1,2,3,6-tetrahydropyridin-2-yl) -propanol-2

The procedure is as in Example 13 starting from the compound of Example 10.

EXAMPLE 15: (1S, 2 "S) -2- (1-Methyl-6-benzoylmethyl-1, 2,3,6-tetrahvdropvridin-2-yl) -l-phenyI-ethanol

Stage A: (IS, 2 "S) -2- [6- (2-Hydroxy-2-phenyl-ethyl) -1-methyl-1,2,3,6-tetrahydro-pyridin-2-yl] -N -methoxy-N-methyl acetamide

The hydrochloride of N, O-dimethylhydroxylamine (3 eq, 88 mg, 0.90 mmol) diluted with anhydrous toluene (1.8 ml) is placed at 0-5 ° C, with argon and stirring. Trimethylaluminum, a 2 M commercial solution in toluene (1.15 eq, 0.52 ml, 1.04 mmol) is added dropwise. When the addition is complete, the ice-water bath is removed and the whole is left stirring for 2 hours. The Weinreb reagent thus prepared is added dropwise under an argon atmosphere to the compound of Example 13 (91 mg, 0.30 mmol) diluted with anhydrous toluene (3 ml). The whole is brought to 80 ° C, still under argon, for 2 h 45. The reaction crude is then poured gently over a hydrochloric acid solution (0.12 N) at 0 ° C. The whole is left under stirring for one to two minutes and then immediately poured back over a solution of sodium bicarbonate at 0 ° C. until the reaction medium is neutral. The organic phase is then extracted with ether then five times with dichloromethane and finally dried over magnesium sulfate. After evaporation of the solvents under reduced pressure, the hydroxyamide obtained (90 mg, 0.28 mmol) is directly reacted.

MS (IC) (isobutane): m / z

319 ([M + H] ⁺ , 100), 216 ([M-CH ₂ CON (Me) OMe] ⁺ , 10)

Stage B: (1S, 2 "S) -2- (1-Methyl-6-benzoylmethyl-1,2,3,6-tetrahydropyridin-2-yl) -1-phenyl-ethanol

0.28 mmol of the hydroxyamide obtained in stage A are placed in anhydrous tetrahydrofuran (3 ml) cooled to -78 ° C under an argon atmosphere and magnetic stirring. The phenyllithium, a 1.6 M commercial solution in the cyclohexane / ether mixture (5 eq, 0.88 ml, 1.41 mmol), is added dropwise. When the addition is complete, the temperature is allowed to rise to 25 ° C. and then stirring is maintained at this temperature overnight. The reaction mixture is poured onto a saturated solution of ammonium chloride at 0 ° C. The organic phase is extracted a first time with ether then with dichloromethane and finally dried over magnesium sulfate. The crude dehydrolobelin is directly transformed into its hydrochloride by treatment with hydrochloric methanol.

The whole is evaporated, taken up in a minimum of methanol and washed three times with heptane. The salt is then quickly filtered on silica eluted with methanol / dichloromethane (0, 0.5, 1 and 2%). Dehydrolobelin hydrochloride is thus isolated, without any other form of purification. The treatment of the hydrochloride in basic medium leads to the inseparable mixture of diastereoisomers in the proportions 85/15 (determined by integration of the protons in NMR). SM (IE): m / z

335 (M ⁺ ', 10), 230 ([M ⁺ '-'COPh], 21), 216 ([M ⁺ '-'CH ₂ COPh], 100), 105 (PhCO ⁺ , 57), 94 (PhOH ^ ', 99)

EXAMPLE 16: (2 "S) -2,6-di (Benzovlmethvl) -1-methvl-L2,3,6-tetrahvdropyridine

The procedure is as in Stage E of Example 1 starting from the compound of Example 15. EXAMPLE 17: (1R, 2 "S) -l- (1-Methvl-6-benzovl ethhl-1.2.3.6-tetrahvdroDvridin-2- yI) -propanol-2

The procedure is as for Example 15 starting from the compound of Example 14.

EXAMPLE 18: (2 ^,, S) -2-Acetylmethyl-6-benzoylmethyl-1-methyl-1,2,3,6-tetrahydropyridine

The procedure is as in Stage E of Example 1 starting from the compound of Example 17.

EXAMPLE 19: (lS, 2 "S, 6" R) -2-ri-Methvl-6- (ll-ethvlenedioxyphenphenethvl-2) -1.2.3 _< 6- tetrahydropyridin-2-yl] -l-phenyl-ethanol

Benzene (5 ml), ethylene glycol in large excess (1 ml) and paratoluene sulfonic acid (1.2 eq, 27 mg, 0.143 mmol) are placed in a small flask. The Dean-Stark is refluxed for approximately 10 minutes to remove any trace of water. The compound of Example 15 is then added in the form of the base (40 mg, 0.119 mmol) diluted in a few milliliters of benzene. After 4 hours at the reflux of the Dean-Stark, the cooled reaction medium is slowly poured onto a sodium bicarbonate solution. The organic phase is extracted a first time with ether then with dichloromethane and finally dried over magnesium sulfate. After evaporation of the solvents under reduced pressure, the acetal is rapidly filtered through alumina eluted with dichloromethane and isolated. Yellow oil SM (IE): m / z 379 (M ⁺ ', 10), 258 ([M ⁺ '-'CH ₂ CH (OH) Ph], 61), 216 ([M ⁺ '-CH ₂ C ( OCH ₂ ) ₂ Ph], 100),

149 (PhC (OCH ₂ ) ₂ 99)

EXAMPLE 20: (2 "S, 6" R) -2-Benzovlmethvl-1-methvl-6- (l.l-ethvlenededioxvphenethyI- 2) -1,2,3,6-tetrahydropyridine

The procedure is as in Stage E of Example 1 starting from the compound of Example 19. PHARMACOLOGICAL STUDY

EXAMPLE A Study of the Capacity of the Compounds of the Invention to Bind to Nicotinic Receptors

The compounds of the present invention were studied in first intention on their capacities to bind to nicotinic receptors using the method of Marks et al. (J.

Pharmacol. Exp. Ther., 1986, 30, 427-436). They showed an interesting affinity for the al receptor using for radio-ligand the ( ¹²⁵ I) -α-bungaro toxin. This activity was confirmed in the technical Xenopus oocytes injected specific mRNAs al ^receptors.

EXAMPLE B: Passive Avoidance Test in the Rat

The study of the facilitative properties of memory was carried out on the passive avoidance test in the Rat during experimental amnesia by cholinergic blocking.

This test was carried out using a box with two compartments, an unlit black and a white very lit by a 25W lamp. The two compartments are separated by a guillotine door and the floor of the black compartment allows to deliver an electric shock

(0.5 mA for 3 seconds). During the learning phase, the animal is placed in the white compartment and the separation door is opened after 60 seconds. After the animal enters the dark compartment, the door is closed and the animal receives an electric shock. During the recollection phase, 24 hours later, the animal is placed again in the white compartment. Under these conditions, a normal rat no longer returns to the dark since it remembers the aversive electric shock. The maximum measurement time for the input latency is fixed at 300 seconds. During amnesia induced by cholinergic blockage, the animal again enters the punished compartment.

During treatment with lobelin or with the compounds of the invention, the rats were protected from experimental amnesia and are therefore not ironed in the punished compartment, which testifies to the integrity of the memory functions of recent events. EXAMPLE C Pharmaceutical composition

Preparation formula for 1000 tablets dosed at 10 mg of the compound of Example 15 (lS, 2 "S) -2- (l-Methyl-6-benzoylmethyl-l, 2,3,6-tetrahydropyridin-2-yl) - 1 -phenyl-ethanol 10 g Wheat starch 15 g

Corn starch 15 g

Lactose 65 g

Magnesium stearate 2 g

Silica 1 g Hydroxypropylcellulose 2 g

Claims

1 / Compounds of formula (I)

in which

X represents a hydrogen atom,

Y represents a hydroxy group, or X and Y together form an oxo group,

R represents a linear or branched (C] -C ₆ ) alkyl group or a phenyl group optionally substituted by one or more halogen atoms or one or more linear or branched (Ci-Ce) alkyl, alkoxy (Cι-C _{6) groups} ), polyhaloalkyl (Cj-

C ₆ ) linear or branched, or hydroxy,

R ¹ represents a hydrogen atom or a group of formula (II):

CT - CR ^J (H)

² / \

X 'Y' in which:

X 'represents a hydrogen atom, Y' represents a hydroxy group, or X 'and Y' simultaneously represent a linear or branched alkoxy group (Cι-C ₆ ), or X 'and Y' together form an oxo group or a linear or branched dioxy (Cj-C) alkylene group,

R ^' represents a linear or branched (C] -C ₆ ) alkoxy group, or a phenyl group optionally substituted by one or more halogen atoms, or one or more linear or branched (Cj-C ₆ ) alkyl groups, alkoxy ( Cι-C ₆ ), linear or branched polyhaloalkyl (CC ₆ ), or hydroxy,

R represents a hydrogen atom, a linear or branched alkyl group (Cι-C ₆ ), optionally substituted by one or more groups, identical or different, optionally substituted aryl, linear or branched alkoxy (Cι-C ₆ ), or hydroxy , 9 being understood that when R and R simultaneously represent a methyl group, X represents a hydrogen atom, Y represents a hydroxy group and R ¹ represents a group of formula (II) where X 'represents a hydrogen atom and Y' a hydroxy group, then R ³ cannot represent a phenyl group,

2 / Compounds of formula (I) according to claim 1 for which X represents a hydrogen atom and Y a hydroxy group.

3 / Compounds of formula (I) according to claim 2 for which R ¹ represents a

₃ group of formula (II): - CH ₂ - C - R

X 'Y'

4 / Compound of formula (I) according to claim 1 which is (lS, 2 "S) -2- (l-Methyl-6-benzoyl-methyl- 1,2,3,6-tetrahydropyridin-2-yl) - 1 -phenyl-ethanol.

5 / Compound of formula (I) according to claim 1 which is (lS, 2 "S, 6" R) -2- [l-Methyl-6- (1,1 -ethylenedioxyphenethyl-2) - 1, 2, 3,6-tetrahydropyridin-2-yl] - 1-phenyl-ethanol.

6 / A process for preparing the compounds of formula (I) according to claim 1 characterized in that a compound of formula (III) is used as starting material:

in which R ⁴ represents a linear or branched alkyl (Cι-C ₆ ) or optionally substituted aryl group, which is reacted with sodium borohydride in the presence of sodium hydroxide to obtain the compound of formula (IV): in which R ⁴ is as defined above, which, subjected to the action of BrZnCH ₂ COOEt, leads to the compound of formula (V)

in which R ⁴ has the same definition as above, which is successively subjected to the action of dimethylthexylchlorosilane then to that of lithium aluminum hydride, to lead to the compound of formula (VI):

in which R ⁴ is as defined above, and Thex represents a group (l, l, 2) -trimethylpropyl, which is oxidized to yield the compound of formula (VII):

in which R and Thex are defined as above, which is subjected to the action of the magnesium RMgBr where R is as defined in formula (I), to lead to the compound of formula (VIII):

(IX): in which R, R and Thex have the same definition as above, all of the compounds (VIII) and (IX) forming the compound of formula (X)

in which R, R, X, Y and Thex are as defined in formula (I) and R ⁴ has the same definition as above, compound of formula (X) which is hydrolyzed in an acid medium, to lead to the compound of formula (11a), special case of the compounds of formula (I):

in which R, X, Y and R are as defined above, which is: either treated, when X represents a hydrogen atom and Y a hydroxy group, with hydrogen in the presence of palladium on carbon, to obtain the compound of formula

(I / b), special case of the compounds of formula (I):

in which R is as defined above, is treated with a diphenylalkylsulfonium tetrafluoroborate of formula (XI):

in which R ⁵ represents a linear or branched alkyl group (Cι-C ₆ ), to result in the compound of formula (XII): in which R, R, R ^' , X and Y are as defined above, which is subjected to the action of potassium tertbutanolate in tertbutanol, to lead to the compound of formula (lie), special case of the compounds of formula ( I):

in which R, X, Y and R are as defined above, which is, in the case where X represents a hydrogen atom and Y a hydroxy group treated with metachloroperbenzoic acid, to obtain the compound of formula (XIII) :

in which R and R have the same definition as above, which is subjected to the action of trifluoroacetic anhydride, to lead to the compound of formula (XIV):

in which R and R are as defined above, which are treated with BrZnCH ₂ COOR ⁶ where R ⁶ represents a linear or branched alkyl group (Cι-C ₆ ), to obtain the compound of formula (I / d), special case of the compounds of formula (I):

in which R, R ⁵ and R ⁶ have the same definition as before, which is successively subjected to the Weinreb reagent N - A1 ^ then to the action

Me- "^"" Me

7 7 of a lithian R-Li where R represents a phenyl group optionally substituted by one or more halogen atoms or one or more alkyl groups (Cι-C ₆ ) linear or branched, alkoxy (Cι-C ₆ ), polyhaloalkyl (Cι-C ₆ ) linear or branched, hydroxy, to lead to the compound of formula (I / e), special case of the compounds of formula (I):

in which R, R and R are as defined above, which is: either subjected to an oxidizing agent, to yield the compound of formula (I / f), special case of the compounds of formula (I):

in which R, R ^" and R have the same definition as above, is subjected to a reducing agent, to lead to the compound of formula (I / g), particular case of the compounds of formula (I):

in which R, R ⁵ and R ⁷ are as defined above, is protected in the form of acetal by the action of an alcohol in an acid medium, to obtain the compound of formula (I / h), special case of the compounds of formula (I):

in which R, R and R are as defined above, and X "and Y" simultaneously represent a linear or branched alkoxy group (Cι-C ₆ ) or together form a linear or branched alkylenedioxy group (Cι-C ₄ ), the compounds (I / a) to (I / h) forming all of the compounds of the invention which are purified, if necessary, according to a conventional purification technique, which can, if desired, be separated in their various optical isomers or salified with a pharmaceutically acceptable acid or base.

7 / Compounds of formula (V), (XII) and (XIII) according to claim 6 useful as intermediates for the synthesis of the compounds of formula (I) according to claim 1.

8 / Pharmaceutical compositions containing at least one compound of formula (I) according to claims 1 to 5 or one of their addition salts with a pharmaceutically acceptable acid in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or vehicles.

9 / Pharmaceutical compositions according to claim 8 containing at least one active principle, according to any one of claims 1 to 5, useful for the treatment of memory deficits linked to cerebral aging and to neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Pick's disease, Korsakoff's disease and frontal and subcortical dementias.